A family of xanthone natural products with antiviral activity has been isolated from plants of the genus Calophyllum. In particular, (+)-calanolide A, isolated from Calophyllum lanigerum var austroconiaceum is a potent inhibitor of HIV-1 reverse transcriptase (Galinis et al, J. Med Chem., 1996, 39, 4507 and references contained therein). The structures of certain such;compounds are as follows. ##STR2##
A number of syntheses of calanolide A have been reported. See, for example, Chenera et al, J. Org. Chem., 1993, 58, 5605; Deshpande et al, J. Org. Chem., 1995, 60, 2964; Rehder and Kepler, Synth. Commun., 1996 26 4005; Khilevich et al, Tetrahedron: Asymmetry, 1996, 7, 3315; Flavin et al, J. Med Chem., 1996, 39, 1303; and Trost and Toste, J. Am. Chem. Soc., 1998, 120, 9074.
Of the reported syntheses of calanolide A, only the syntheses of Deshpande et al and Trost and Toste are asymmetric. In particular, only the synthesis of Trost and Toste uses asymmetric catalysis in the key stereodifferentiating reaction, which comprises palladium-catalysed asymmetric allylic substitution of tiglyl methyl carbonate with 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chroman-8-one. Following asymmetric allylic substitution, benzylic oxidation with DDQ is used to introduce the unsaturation in the C ring, and further steps to calanolide B comprise diastereoselective hydroboration, Dess Martin oxidation, and cyclisation with zinc chloride. Calanolide A is obtained by Mitsunobu inversion of calanolide B. This methodology is readily extended to the preparation of natural and unnatural analogues of calanolides A and B.
An alternative nucleophile in the asymmetric allylic substitution reaction of Trost and Toste or other D-ring annulation procedures, which would result in a shorter overall synthesis by elimination of the C-ring dehydrogenation step, would be 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (in which the C-ring double bond is already present). This compound was originally prepared by unselective 1-step chromene annulation of 4-propyl-5,7-dihydroxycoumarin (Games and Haskins, J. Chem. Soc. Chem. Commun., 1971, 1005).
The preparation of 5,7-dihydroxycoumarin monosulphonate esters by direct sulphonylation of 5,7-dihydroxycoumarin has been reported by Desai and Parghi,J Indian Chem. Soc., 1956, 33, 661. The yield obtained for the preparation of 4-methyl-8-hydroxy-7-coumarinyl-4-toluenesulphonate by this procedure was 36%.